A High Throughput Approach for Designing Polymers That Mimic the TRAIL Protein
Zihao Li, Zifei Han, Martina H. Stenzel, Robert Chapman
Abstract
We have leveraged a high throughput approach to design a fully synthetic polymer mimic of the chemotherapeutic protein “TRAIL”. Our design enables the synthesis of libraries of star-shaped polymers presenting exactly one receptor binding peptide at the end of each arm with no purification steps. Clear structure–activity relationships in screening for receptor binding and the apoptotic activity on colon cancer lines (COLO205) led us to identify trivalent structures, ∼1.5 nm in hydrodynamic radius as the best mimics. These showed IC50 values ∼2 μM and resulted in the elevated levels of caspase-8 expected from this mechanism of cell death. Our results demonstrate the potential for HTP screening methods to be used in the design of polymers that can mimic a whole range of complex therapeutic proteins.